About
Articles by Carla
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2015-2016 MGH Postdocs Association Volunteers Appreciation Day
2015-2016 MGH Postdocs Association Volunteers Appreciation Day
By Carla D'Avanzo, PhD
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MGH Postdoc Association Pilot Mentoring Program
MGH Postdoc Association Pilot Mentoring Program
By Carla D'Avanzo, PhD
Activity
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🌟 What an incredible day at Villa Beretta Rehabilitation Research Innovation Institute I am deeply grateful to have had the opportunity to present…
🌟 What an incredible day at Villa Beretta Rehabilitation Research Innovation Institute I am deeply grateful to have had the opportunity to present…
Liked by Carla D'Avanzo, PhD
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At @Sanofi, AI isn't just a tool—it's interwoven into every step of our drug development journey. The use of virtual patient populations, or…
At @Sanofi, AI isn't just a tool—it's interwoven into every step of our drug development journey. The use of virtual patient populations, or…
Liked by Carla D'Avanzo, PhD
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Grow with AI and Sanofi! Unique opportunity in the development team.
Grow with AI and Sanofi! Unique opportunity in the development team.
Liked by Carla D'Avanzo, PhD
Experience & Education
Licenses & Certifications
Volunteer Experience
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Social Media and Event Manager
Cancer Education and Research Institute
- 6 months
Health
After extensive experience in networking and event management, social media strategies, and community management, I'm very excited to use my experience and skills toward the great mission of Cancer Research Simplified
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TrialMatch@ Lead Volunteer
Alzheimer's Association®
- 4 years 1 month
Health
Lead Volunteers speak with in-depth knowledge about clinical trials and the TrialMatch@program.
Lead Volunteers are responsible for answering any questions that basic volunteers cannot answer. They also oversee day-of set-up for the event.
- Supervise TrialMatch@ information table at one of three Walk to End Alzheimer's events.
- Answer questions from Walk attendees with in-depth knowledge about clinical trials and TrialMatch@
. Oversee TrialMatch@ Outreach Volunteers.
…Lead Volunteers speak with in-depth knowledge about clinical trials and the TrialMatch@program.
Lead Volunteers are responsible for answering any questions that basic volunteers cannot answer. They also oversee day-of set-up for the event.
- Supervise TrialMatch@ information table at one of three Walk to End Alzheimer's events.
- Answer questions from Walk attendees with in-depth knowledge about clinical trials and TrialMatch@
. Oversee TrialMatch@ Outreach Volunteers.
. Coordinate with Walk staff to ensure that TrialMatch@ table is set up in advance of event.
- Direct attendees to TrialMatch@ Helpline when necessary t Represent Alzheimer's Association in a friendly and professional manner. -
Event Coordinator - "Healthy Brain; Enlightened Brain" - Deepak Chopra&Rudy Tanzi
HUBweek
- Present 6 years 10 months
Science and Technology
Coordinating event logistics
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Registration Coordinator at "The Art of Talking Science" by Mass General Research Institute
HUBweek
- Present 5 years 10 months
Science and Technology
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2018 My Giving Helps: MGH Fund + United Way Champion
Massachusetts General Hospital
- Present 5 years 11 months
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Volunteer Event Committee Member - Young ProfessionAlz
Alzheimer's Association, Massachusetts/New Hampshire Chapter
- Present 5 years 6 months
Health
Young ProfessionALZ is dedicated to raising awareness of Alzheimer's disease and related dementias through volunteering, support, and advocacy to further the mission of the MA/NH Chapter of the Alzheimer's Association.
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Judge and Coach at Citywide Boston Science and Engineering Fair and Region VI/BPS Science Fair
Boston Public Schools
- 3 years 1 month
Science and Technology
Boston Public Schools hosted the 2018-2020 Citywide Boston Science and Engineering Fair, held at Northeastern University in collaboration with the Center for STEM Education.
Provide coaching feedback on student projects and their presentations.
Students are from the Boston Citywide Science Fair and they have been invited to exhibit their projects from the 73rd Region VI/BPS Science Fair. -
Judge Poster Session at the National Collegiate Research Conference
Harvard College Undergraduate Research Organization (HCURA)
- 4 years 1 month
Education
The National Collegiate Research Conference is a large-scale forum held at Harvard University where exceptional undergraduate students from across the United States come together to share their research across the natural sciences, social sciences, and humanities, as well as to hear renowned speakers in academia, policy, and industry. In the past, our keynote speakers have included Marcia McNutt, Editor in Chief of Science,Steven Pinker, psychologist and writer, Robert Langer, biotechnologist…
The National Collegiate Research Conference is a large-scale forum held at Harvard University where exceptional undergraduate students from across the United States come together to share their research across the natural sciences, social sciences, and humanities, as well as to hear renowned speakers in academia, policy, and industry. In the past, our keynote speakers have included Marcia McNutt, Editor in Chief of Science,Steven Pinker, psychologist and writer, Robert Langer, biotechnologist and engineer, and Jill Abramson, executive editor of the New York Times.
This year, the conference welcomed approximately 200 participants from nearly 70 universities both domestically and internationally. Through this conference, they hope to expand the perspective of undergraduate researchers through exposure to diverse research fields and to create a more tight-knit undergraduate research community.
Judges were responsible for judging at least one session which would involve approximately 3-4 posters in a timespan of an hour and a half. Scoring and rubric system were provided, and their responsibilities entailed speaking with the student and providing a short written evaluation. -
Volunteer Scientific Event Manager - Brain Awareness Week - MGH Youth Scholars
The Dana Foundation
- 2 years 3 months
9th grader MGH Youth Scholars are invited to visit the Genetics and Aging Unit at Mass General Research Institute to learn more about brain health and neuroscience research.
The event has been split in two days. During day 1 I gave a short oral presentation to introduce the brain and the neuroscience followed by conversations with different lab members that shared details on their daily life in the lab, their job role and research project. Day 2 was a hands-on experience with rotation…9th grader MGH Youth Scholars are invited to visit the Genetics and Aging Unit at Mass General Research Institute to learn more about brain health and neuroscience research.
The event has been split in two days. During day 1 I gave a short oral presentation to introduce the brain and the neuroscience followed by conversations with different lab members that shared details on their daily life in the lab, their job role and research project. Day 2 was a hands-on experience with rotation between 3 stations: confocal microscope imaging, cell culture and molecular biology techniques. -
Chapter Correspondent and Social Media Manager Volunteer
The Biotech Connection at Boston (BCB)
- 1 year
BCB bridges the gap between academia and industry by bringing together scholars and innovator from across disciplines within the life science industry to spark collaboration on cutting edge research. At BCB we aim to connect the diverse members of Boston's biotech community to continue to drive innovation and give companies access to highly qualified talent.
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Board Member
Harvard Italian Society
- 8 months
The mission of the Italian Society is to create a community of people at Harvard University interested in: promoting Italian culture and heritage; supporting the Italian language; promoting better EU-US transatlantic relationships through a mediation role within the EU framework; organizing discussion groups and events, conferences and exhibitions, and inviting guest speakers.
In addition, the Italian Society will make all efforts to establish a connection with interested institutions…The mission of the Italian Society is to create a community of people at Harvard University interested in: promoting Italian culture and heritage; supporting the Italian language; promoting better EU-US transatlantic relationships through a mediation role within the EU framework; organizing discussion groups and events, conferences and exhibitions, and inviting guest speakers.
In addition, the Italian Society will make all efforts to establish a connection with interested institutions in the Greater Boston Area and nation-wide, like Universities, the Italian Consulate, and language schools. -
Marketing Associate Volunteer
STEM Career Services
- 3 months
Education
STEM Career Services is a career coaching company that specializes in working with STEM (science, technology, engineering and math) graduates and postdocs who are looking to start a career outside of the academic or laboratory environment. We are expert mentors and professionals with invaluable experience in government consulting; management consulting; biotech, pharmaceuticals and medical device industries; Federal government and nonprofits. STEM Career Services offers career workshops…
STEM Career Services is a career coaching company that specializes in working with STEM (science, technology, engineering and math) graduates and postdocs who are looking to start a career outside of the academic or laboratory environment. We are expert mentors and professionals with invaluable experience in government consulting; management consulting; biotech, pharmaceuticals and medical device industries; Federal government and nonprofits. STEM Career Services offers career workshops, one-‐on-‐one coaching and small group coaching.
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Scientific Event Committee- Alzheimer’s from the benches: Where we are today and hope for tomorrow
North Shore Tech Council (NSTC)
- 11 months
Member of the Organizing Committee, responsible for:
- program and speakers
- promotion materials and marketing
- local organization -
Mentor at Mass General Postdoc Association Mentoring Circle
Mass General Research Institute
- 1 year
Mentor of 5 MGH postdocs for 1 year term - Mentoring Circle program at Mass General organized by Mass General Postdocs Association (MGPA)
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Volunteer Marketing Committee Member
WEST - Women in the Enterprise of Science and Technology
- 6 months
WEST - Promoting women's careers, preparing tomorrow's leaders
Help planning and executing marketing strategy for WEST
Publications
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A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease
Nature Neuroscience
Alzheimer’s disease (AD) is characterized by beta-amyloid accumulation, phosphorylated tau formation, hyper activation of glial cells, and neuronal loss. The mechanisms of AD pathogenesis, however, remain poorly understood, partially due to the lack of relevant models that can comprehensively recapitulate multistage intercellular interactions in human AD brains. Here we present a new three-dimensional (3D) human AD triculture model using neurons, astrocytes, and microglia in a 3D microfluidic…
Alzheimer’s disease (AD) is characterized by beta-amyloid accumulation, phosphorylated tau formation, hyper activation of glial cells, and neuronal loss. The mechanisms of AD pathogenesis, however, remain poorly understood, partially due to the lack of relevant models that can comprehensively recapitulate multistage intercellular interactions in human AD brains. Here we present a new three-dimensional (3D) human AD triculture model using neurons, astrocytes, and microglia in a 3D microfluidic platform. Our model provided key representative AD features: beta-amyloid aggregation, phosphorylated tau accumulation, and neuroinflammatory activity. In particular, the model mirrored microglial recruitment, neurotoxic activities such as axonal cleavage, and NO release damaging AD neurons and astrocytes. Our model will serve to facilitate the development of more precise human brain models for basic mechanistic studies in neural–glial interactions and drug discovery.
Other authorsSee publication -
β-Secretase BACE1 promotes surface expression and function of Kv3.4 at hippocampal mossy fiber synapses
The Journal of Neuroscience
β-Secretase BACE1 is infamous for its crucial role in the pathogenesis of Alzheimer's disease, but its physiological functions in the intact nervous system are only gradually being unveiled. Here, we extend previous work implicating BACE1 in the expression and function of voltage-gated Na+ and K+ channels. Specifically, we characterize Kv3.4, a presynaptic K+ channel required for action potential repolarization, as a novel interaction partner of BACE1 at the mossy fiber-CA3 synapse of the…
β-Secretase BACE1 is infamous for its crucial role in the pathogenesis of Alzheimer's disease, but its physiological functions in the intact nervous system are only gradually being unveiled. Here, we extend previous work implicating BACE1 in the expression and function of voltage-gated Na+ and K+ channels. Specifically, we characterize Kv3.4, a presynaptic K+ channel required for action potential repolarization, as a novel interaction partner of BACE1 at the mossy fiber-CA3 synapse of the hippocampus. BACE1 promotes surface expression of Kv3.4 at mossy fiber terminals, most likely by physically associating with the channel protein in a non-enzymatic fashion. We advance the BACE1-Kv3.4 interaction as a mechanism to strengthen the temporal control over transmitter release from mossy fiber terminals.
Other authorsSee publication -
Human Neurospheroid Arrays for In Vitro Studies of Alzheimer’s Disease
Scientific Reports
Neurospheroids are commonly used for in vitro disease modeling and drug screening. However, the heterogeneity in size of the neurospheroids mixtures available through current methods limits their utility when employed for basic mechanistic studies of neurodegenerative diseases or screening for new interventions. Here, we generate neurospheroids from immortalized neural progenitor cells and human induced pluripotent stem cells that are uniform in size, into large-scale arrays. In proof of…
Neurospheroids are commonly used for in vitro disease modeling and drug screening. However, the heterogeneity in size of the neurospheroids mixtures available through current methods limits their utility when employed for basic mechanistic studies of neurodegenerative diseases or screening for new interventions. Here, we generate neurospheroids from immortalized neural progenitor cells and human induced pluripotent stem cells that are uniform in size, into large-scale arrays. In proof of concept experiments, we validate the neurospheroids array as a sensitive and robust tool for screening compounds over extended time. We show that when suspended in three-dimensional extracellular matrix up to several weeks, the stem cell-derived neurospheroids display extensive neurite outgrowth and extend thick bundles of dendrites outward. We also cultivate genetically-engineered stem cell-derived neurospheroids with familial Alzheimer’s disease mutations for eight weeks in our microarray system. Interestingly, we observed robust accumulation of amyloid-β and phosphorylated tau, key hallmarks of Alzheimer’s disease. Overall, our in vitro model for engineering neurospheroid arrays is a valuable tool for studying complex neurodegenerative diseases and accelerating drug discovery.
Other authorsSee publication -
Three-Dimensional Models of the Human Brain Development and Diseases
Advanced Healthcare Materials
Neurological disorders represent a significant proportion of human diseases; however, understanding brain pathology is challenging, in part because of the complexity of the brain structure and function. Sophisticated models are required to reconstitute the tangled architecture and complex functions of brain cells. Here we review the most recent advances, chalenges, and future directions of 3D cell culture systems for modeling the human brain.
Other authorsSee publication -
Three-Dimensional Cultures of Human Neural Stem Cells: An Application for Modeling Alzheimer’s Disease Pathogenesis
Springer Protocols
A three-dimensional (3D) cell culture system allows cells to grow and attach to their environments in all three directions. As opposed to the conventional method of growing cells in a flat environment on a petri dish (2D), the 3D cultures can closely mimic the in vivo cellular environment. Recently, we developed a novel cell culture model system of Alzheimer’s disease (AD) by employing a 3D culture setting. In this model, human neural progenitor cells harboring multiple familial AD (fAD)…
A three-dimensional (3D) cell culture system allows cells to grow and attach to their environments in all three directions. As opposed to the conventional method of growing cells in a flat environment on a petri dish (2D), the 3D cultures can closely mimic the in vivo cellular environment. Recently, we developed a novel cell culture model system of Alzheimer’s disease (AD) by employing a 3D culture setting. In this model, human neural progenitor cells harboring multiple familial AD (fAD) mutations were differentiated in a 3D Matrigel. Using this 3D culture model, we have shown, for the first time, that fAD mutations can induce β-amyloid plaque and tau tangle pathologies. These two major pathological hallmarks of AD have not yet been achieved in current AD mouse models. In this chapter, we describe instructions and troubleshooting for establishing 3D human cell culture models that can be used to analyze β-amyloid and tau pathology in a dish.
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Alzheimer’s in 3D culture: Challenges and perspectives
Bioessays
Recently, we recapitulated key events of Alzheimer’s disease pathogenesis in a 3D human stem cells culture system. This model enhances beta-amyloid accumulation and neurofibrillary tau tangles (NFT), providing a powerful cellular model for Alzheimer’s disease. In this review, we discuss the current
progress of modeling neurodegenerative diseases in 3D cultures.Other authorsSee publication -
Synaptotagmins interact with APP and promote Aβ generation
Molecular Neurodegeneration
Our study identifies Syt-1, -2 and -9 as novel APP interacting proteins and demonstrates that Syt-1 is a physiological interactor of APP. We narrowed down the Syt binding site to the 108 aminoacid E1-KPI domain linker region of APP. Moreover, we showed that both Syt-1 and Syt-9 increased Aβ levels likely via BACE1-mediated APP processing. Thus, these Syts may play an important role in Alzheimer’s disease pathology. Overall, our studies reveal an important novel function of the synaptic vesicle…
Our study identifies Syt-1, -2 and -9 as novel APP interacting proteins and demonstrates that Syt-1 is a physiological interactor of APP. We narrowed down the Syt binding site to the 108 aminoacid E1-KPI domain linker region of APP. Moreover, we showed that both Syt-1 and Syt-9 increased Aβ levels likely via BACE1-mediated APP processing. Thus, these Syts may play an important role in Alzheimer’s disease pathology. Overall, our studies reveal an important novel function of the synaptic vesicle proteins Synaptotagmins in regulating Aβ generation.
Other authorsSee publication -
A 3D human neural cell culture system for modeling Alzheimer’s disease
Nature Protocols
Stem cell technology has facilitated the development of human cell culture models of disease that can be used to study pathogenesis and test therapeutic candidates. These models hold particular promise for complex neurological diseases such as Alzheimer’s disease (AD) because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the design and characterization of a novel three-dimensional (3D) culture system that exhibits key events in the…
Stem cell technology has facilitated the development of human cell culture models of disease that can be used to study pathogenesis and test therapeutic candidates. These models hold particular promise for complex neurological diseases such as Alzheimer’s disease (AD) because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the design and characterization of a novel three-dimensional (3D) culture system that exhibits key events in the pathogenic cascade of AD, including extracellular aggregation of amyloid β peptides and accumulation of hyperphosphorylated/aggregated tau protein. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCs) with familial AD (FAD) mutations, the differentiation of the hNPCs in a 3D Matrigel matrix, and the analysis of AD pathogenesis in this model. The same principles may be applicable to models of other inherited neurodegenerative diseases characterized by the aberrant aggregation of misfolded proteins.
Other authorsSee publication -
Gamma-secretase modulators reduce endogenous amyloid beta42 levels in human neural progenitor cells without altering neuronal differentiation
Faseb J
Soluble γ-secretase modulators (SGSMs) selectively decrease toxic amyloid β (Aβ) peptides (Aβ42). However, their effect on the physiologic functions of γ-secretase has not been tested in human model systems. γ-Secretase regulates fate determination of neural progenitor cells. Thus, we studied the impact of SGSMs on the neuronal differentiation of ReNcell VM (ReN) human neural progenitor cells (hNPCs). Quantitative PCR analysis showed that treatment of neurosphere-like ReN cell aggregate…
Soluble γ-secretase modulators (SGSMs) selectively decrease toxic amyloid β (Aβ) peptides (Aβ42). However, their effect on the physiologic functions of γ-secretase has not been tested in human model systems. γ-Secretase regulates fate determination of neural progenitor cells. Thus, we studied the impact of SGSMs on the neuronal differentiation of ReNcell VM (ReN) human neural progenitor cells (hNPCs). Quantitative PCR analysis showed that treatment of neurosphere-like ReN cell aggregate cultures with γ-secretase inhibitors (GSIs), but not SGSMs, induced a 2- to 4-fold increase in the expression of the neuronal markers Tuj1 and doublecortin. GSI treatment also induced neuronal marker protein expression, as shown by Western blot analysis. In the same conditions, SGSM treatment selectively reduced endogenous Aβ42 levels by ∼80%. Mechanistically, we found that Notch target gene expressions were selectively inhibited by a GSI, not by SGSM treatment. We can assert, for the first time, that SGSMs do not affect the neuronal differentiation of hNPCs while selectively decreasing endogenous Aβ42 levels in the same conditions. Our results suggest that our hNPC differentiation system can serve as a useful model to test the impact of GSIs and SGSMs on both endogenous Aβ levels and γ-secretase physiologic functions including endogenous Notch signaling.
Other authorsSee publication -
A three-dimensional human neural cell culture model of Alzheimer's disease.
Nature
To date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated…
To date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.
Other authorsSee publication -
BACE1 activity regulates cell surface contactin-2 levels.
Molecular Neurodegeneration
BACKGROUND:
Although BACE1 is a major therapeutic target for Alzheimer's disease (AD), potential side effects of BACE1 inhibition are not well characterized. BACE1 cleaves over 60 putative substrates, however the majority of these cleavages have not been characterized. Here we investigated BACE1-mediated cleavage of human contactin-2, a GPI-anchored cell adhesion molecule.
RESULTS:
Our initial protein sequence analysis showed that contactin-2 harbors a strong putative BACE1 cleavage…BACKGROUND:
Although BACE1 is a major therapeutic target for Alzheimer's disease (AD), potential side effects of BACE1 inhibition are not well characterized. BACE1 cleaves over 60 putative substrates, however the majority of these cleavages have not been characterized. Here we investigated BACE1-mediated cleavage of human contactin-2, a GPI-anchored cell adhesion molecule.
RESULTS:
Our initial protein sequence analysis showed that contactin-2 harbors a strong putative BACE1 cleavage site close to its GPI membrane linker domain. When we overexpressed BACE1 in CHO cells stably transfected with human contactin-2, we found increased release of soluble contactin-2 in the conditioned media. Conversely, pharmacological inhibition of BACE1 in CHO cells expressing human contactin-2 and mouse primary neurons decreased soluble contactin-2 secretion. The BACE1 cleavage site mutation 1008MM/AA dramatically impaired soluble contactin-2 release. We then asked whether contactin-2 release induced by BACE1 expression would concomitantly decrease cell surface levels of contactin-2. Using immunofluorescence and surface-biotinylation assays, we showed that BACE1 activity tightly regulates contactin-2 surface levels in CHO cells as well as in mouse primary neurons. Finally, contactin-2 levels were decreased in Alzheimer's disease brain samples correlating inversely with elevated BACE1 levels in the same samples.
CONCLUSION:
Our results clearly demonstrate that mouse and human contactin-2 are physiological substrates for BACE1. BACE1-mediated contactin-2 cleavage tightly regulates the surface expression of contactin-2 in neuronal cells. Given the role of contactin-2 in cell adhesion, neurite outgrowth and axon guidance, our data suggest that BACE1 may play an important role in these physiological processes by regulating contactin-2 surface levels.Other authorsSee publication -
The E280A presenilin mutation reduces voltage-gated sodium channel levels in neuronal cells
Neurodegenerative Diseases
BACKGROUND:
Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/γ-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/γ-secretase cleaves voltage-gated sodium channel β2-subunits (Navβ2), releases the intracellular domain of Navβ2 (β2-ICD), and thereby, increases intracellular sodium channel α-subunit Nav1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Navβ2 cleavages and Nav1.1 levels.
OBJECTIVE:
It…BACKGROUND:
Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/γ-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/γ-secretase cleaves voltage-gated sodium channel β2-subunits (Navβ2), releases the intracellular domain of Navβ2 (β2-ICD), and thereby, increases intracellular sodium channel α-subunit Nav1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Navβ2 cleavages and Nav1.1 levels.
OBJECTIVE:
It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Navβ2 processing and Nav1.1 levels in neuronal cells.
METHODS:
We first generated B104 rat neuroblastoma cells stably expressing Navβ2 and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or ΔE9), or PS1 with a non-FAD mutation (D333G). Navβ2 processing and Nav1.1 protein and mRNA levels were then analyzed by Western blot and real-time RT-PCR, respectively.
RESULTS:
The FAD-linked E280A mutation significantly decreased PS/γ-secretase-mediated processing of Navβ2 as compared to wtPS1 controls, both in cells and in a cell-free system. Nav1.1 mRNA and protein levels, as well as the surface levels of Nav channel α-subunits, were also significantly reduced in PS1(E280A) cells.
CONCLUSION:
Our data indicate that the FAD-linked PS1(E280A) mutation decreases Nav channel levels by partially inhibiting the PS/γ-secretase-mediated cleavage of Navβ2 in neuronal cells.
Other authorsSee publication -
A new concept: Aβ1-42 Generates A Hyperfuctional Proteolytic NCX3 that Delays Caspase12 Activation and Neuronal Death.
J.Neuroscience
Although the amyloid-β(1-42) (Aβ(1-42)) peptide involved in Alzheimer's disease is known to cause a dysregulation of intracellular Ca(2+) homeostasis, its molecular mechanisms still remain unclear. We report that the extracellular-dependent early increase (30 min) in intracellular calcium concentration ([Ca(2+)](i)), following Aβ(1-42) exposure, caused the activation of calpain that in turn elicited a cleavage of the Na(+)/Ca(2+) exchanger isoform NCX3. This cleavage generated a hyperfunctional…
Although the amyloid-β(1-42) (Aβ(1-42)) peptide involved in Alzheimer's disease is known to cause a dysregulation of intracellular Ca(2+) homeostasis, its molecular mechanisms still remain unclear. We report that the extracellular-dependent early increase (30 min) in intracellular calcium concentration ([Ca(2+)](i)), following Aβ(1-42) exposure, caused the activation of calpain that in turn elicited a cleavage of the Na(+)/Ca(2+) exchanger isoform NCX3. This cleavage generated a hyperfunctional form of the antiporter and increased NCX currents (I(NCX)) in the reverse mode of operation. Interestingly, this NCX3 calpain-dependent cleavage was essential for the Aβ(1-42)-dependent I(NCX) increase. Indeed, the calpain inhibitor calpeptin and the removal of the calpain-cleavage recognition sequence, via site-directed mutagenesis, abolished this effect. Moreover, the enhanced NCX3 activity was paralleled by an increased Ca(2+) content in the endoplasmic reticulum (ER) stores. Remarkably, the silencing in PC-12 cells or the knocking-out in mice of the ncx3 gene prevented the enhancement of both I(NCX) and Ca(2+) content in ER stores, suggesting that NCX3 was involved in the increase of ER Ca(2+) content stimulated by Aβ(1-42). By contrast, in the late phase (72 h), when the NCX3 proteolytic cleavage abruptly ceased, the occurrence of a parallel reduction in ER Ca(2+) content triggered ER stress, as revealed by caspase-12 activation. Concomitantly, the late increase in [Ca(2+)](i) coincided with neuronal death. Interestingly, NCX3 silencing caused an earlier activation of Aβ(1-42)-induced caspase-12. Indeed, in NCX3-silenced neurons, Aβ(1-42) exposure hastened caspase-dependent apoptosis, thus reinforcing neuronal cell death. These results suggest that Aβ(1-42), through Ca(2+)-dependent calpain activation, generates a hyperfunctional form of NCX3 that, by increasing Ca(2+) content into ER, delays caspase-12 activation and thus neuronal death.
Other authorsSee publication -
Silencing or knocking out the Na(+)/Ca(2+) exchanger-3 (NCX3) impairs oligodendrocyte differentiation.
Cell Death Differ.
Changes in intracellular [Ca(2+)](i) levels have been shown to influence developmental processes that accompany the transition of human oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes and are required for the initiation of the myelination and re-myelination processes. In the present study, we explored whether calcium signals mediated by the selective sodium calcium exchanger (NCX) family members NCX1, NCX2, and NCX3, play a role in oligodendrocyte maturation…
Changes in intracellular [Ca(2+)](i) levels have been shown to influence developmental processes that accompany the transition of human oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes and are required for the initiation of the myelination and re-myelination processes. In the present study, we explored whether calcium signals mediated by the selective sodium calcium exchanger (NCX) family members NCX1, NCX2, and NCX3, play a role in oligodendrocyte maturation. Functional studies, as well as mRNA and protein expression analyses, revealed that NCX1 and NCX3, but not NCX2, were divergently modulated during OPC differentiation into oligodendrocyte phenotype. In fact, whereas NCX1 was downregulated, NCX3 was strongly upregulated during oligodendrocyte development. The importance of calcium signaling mediated by NCX3 during oligodendrocyte maturation was supported by several findings. Indeed, whereas knocking down the NCX3 isoform in OPCs prevented the upregulation of the myelin protein markers 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) and myelin basic protein (MBP), its overexpression induced an upregulation of CNPase and MBP. Furthermore, NCX3-knockout mice showed not only a reduced size of spinal cord but also marked hypo-myelination, as revealed by decrease in MBP expression and by an accompanying increase in OPC number. Collectively, our findings indicate that calcium signaling mediated by NCX3 has a crucial role in oligodendrocyte maturation and myelin formation.
Other authorsSee publication
Honors & Awards
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Travel fellowship BACE meeting
NIH
Travel award to BACE meeting in Kloster Seen, Germany September 2016
Languages
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English
Professional working proficiency
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Italian
Native or bilingual proficiency
Organizations
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Sfn
member
- Present -
SINS
member
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More activity by Carla
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I have transitioned to a new role where I'll continue working on water projects, now focusing on South Asia after my experience in Latin…
I have transitioned to a new role where I'll continue working on water projects, now focusing on South Asia after my experience in Latin…
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I couldn't be more honored than to be invited to join the Board of Directors of Cohort Sistas. Very excited to support our impactful mentoring and…
I couldn't be more honored than to be invited to join the Board of Directors of Cohort Sistas. Very excited to support our impactful mentoring and…
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It was a pleasure joining my industry colleagues Samarth Virk, Jalpa Dave and Susan Nemetz to discuss the The Digital Future at Future Pharma 2024!
It was a pleasure joining my industry colleagues Samarth Virk, Jalpa Dave and Susan Nemetz to discuss the The Digital Future at Future Pharma 2024!
Liked by Carla D'Avanzo, PhD
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Thrilled to have been invited to give a talk for the 2024 session of the ICPP conference organized in Niagara Falls, USA! A nice opportunity to meet…
Thrilled to have been invited to give a talk for the 2024 session of the ICPP conference organized in Niagara Falls, USA! A nice opportunity to meet…
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POSTDOC POSITION AVAILABLE AT IEO, MILAN Interested in understanding the role of chromosome instability and micronuclei in cancer development? We…
POSTDOC POSITION AVAILABLE AT IEO, MILAN Interested in understanding the role of chromosome instability and micronuclei in cancer development? We…
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On June 20th I had the unique opportunity to present my decade-long research on French domesitic interiors, the evolution of the French apartment and…
On June 20th I had the unique opportunity to present my decade-long research on French domesitic interiors, the evolution of the French apartment and…
Liked by Carla D'Avanzo, PhD
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Our new publication describing a clinical trial assessing the effects of aerobic exercise on brain age and brain health: https://lnkd.in/epyPiPBq
Our new publication describing a clinical trial assessing the effects of aerobic exercise on brain age and brain health: https://lnkd.in/epyPiPBq
Liked by Carla D'Avanzo, PhD
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It was great fun to run the 2024’s edition of the Workshop in Systems Immunology at FOCIS in San Francisco - this year celebrating its 10th…
It was great fun to run the 2024’s edition of the Workshop in Systems Immunology at FOCIS in San Francisco - this year celebrating its 10th…
Liked by Carla D'Avanzo, PhD
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It was a great pleasure to give a talk last Friday in Montpellier for the French Association of crystallography ; AFC. A very nice opportunity to…
It was a great pleasure to give a talk last Friday in Montpellier for the French Association of crystallography ; AFC. A very nice opportunity to…
Liked by Carla D'Avanzo, PhD
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Welcome to Adam Rosenberg as the new Chair of VectorY! Boston-based Mr Rosenberg brings over 20 years of experience in building and leading life…
Welcome to Adam Rosenberg as the new Chair of VectorY! Boston-based Mr Rosenberg brings over 20 years of experience in building and leading life…
Liked by Carla D'Avanzo, PhD
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This year I’m proud to be a Sanofi mentor for the next generation of STEM leaders! Thanks to the Sanofi AIM (Achieve. Ignite. Mentor) Program Site…
This year I’m proud to be a Sanofi mentor for the next generation of STEM leaders! Thanks to the Sanofi AIM (Achieve. Ignite. Mentor) Program Site…
Shared by Carla D'Avanzo, PhD
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It was a great pleasure for me and Alex Sverdlov to discuss our new book on #genetherapy with Rosemary Pennington and A. John Bailer from Miami…
It was a great pleasure for me and Alex Sverdlov to discuss our new book on #genetherapy with Rosemary Pennington and A. John Bailer from Miami…
Liked by Carla D'Avanzo, PhD
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